Hereditary non-polyposis colon cancer/Lynch syndrome (HNPCC) is characterized by an autosomal dominant inheritance pattern of early onset colorectal, uterine, urological, and upper gastrointestinal malignancies. Despite the discovery of several mismatch repair genes underlying this syndrome, approximately 40% of HNPCC/Lynch syndrome families have no identifiable germline mutations in any of the known candidate genes. We have analyzed 42 HNPCC pedigrees with no identifiable candidate gene germline mutations using FASTSLINK to estimate statistical genetic power to obtain linkage. We have begun performing locus- targeted and whole autosomal genome linkage analysis on the statistically most powerful subset of these families. In addition, we are looking for additional proteins which interact with the mammalian DNA mismatch repair system, using a far Western filter-screening approach.